The rapid progression of the SARS-CoV-2 pandemic and associated COVID-19 disease in the first 3 months of 2020 highlight the urgent need for research to understand the pathogenesis of the disease at the cellular level and how the immune system responds to this infection. Although persons of any age and gender can be infected and develop symptomatic disease, patients 60 years or older with or without co-morbidities are particularly prone to severe consequences of the infection ultimately leading to death. While data from all over the world are beginning to give a better picture about the epidemiology and clinical progression of COVID-19, limited information about the pathogenesis of the disease at the cellular level is available. A recent report showed that the SARS-CoV-2 viral spike protein (S) uses the SARS-CoV receptor ACE2 for binding and that the mammalian serine protease TMPRSS2 primes the S protein to allow viral fusion with the cell membrane and viral entry. However, little is known about how viral binding and entry affects specific immune cells, and what pathways are involved in the immune response to SARS-CoV-2 and whether differences in this immune response could explain the increased propensity of individuals aged >60 to develop severe consequences of infection. We will begin to address this knowledge gap via a multi-omics approach using: 1) primary human PBMCs isolated from normal young and aged individuals and subsequently treated in vitro with the SARS-CoV-2 S protein or infected with SARS-CoV-2 and 2) samples from patients infected with SARS-CoV-2.